Temporomandibular joint (TMJ) articular cartilage injuries do not heal, resulting in joint degeneration that interferes with speaking and eating. The TMJ articular surface is unique because it consists of hyaline cartilage overlaid with a proliferative cell and a fibrocartilage layer. TMJ cartilage regeneration has received little attention. Hyaline cartilage regeneration in other joints has been subject to extensive research; however, no effective clinical therapy has been produced. In response, the cartilage regeneration paradigm has begun to shift from empirical approaches to rational biomimetic designs based on developmental biology concepts. Successful healing in adults, such as bone healing, recapitulates tissue morphogenesis and is orchestrated by a cascade of growth factors that induce chemotaxis, proliferation, and differentiation of endogenous mesenchymal stem cells (MSC). Local MSC sources for synovial joints include the synovial membrane (sMSC) and the bone marrow (bMSC). My goal is to develop an in situ therapy, based on endogenous MSC recruitment that will orchestrate regeneration of durable TMJ cartilage. My preliminary data show that 1) synovial cells isolated from the rabbit TMJ exhibit chondrogenesis and ostogenesis in vitro; 2) TGFa and PDGF-bb induce chemotaxis and FGF-2 induces proliferation by synovial cells in vitro; and 3) growth factor delivery in rabbit knee osteochondral defects induced regeneration of immature hyaline cartilage. My guiding hypothesis is that robust in situ cartilage regeneration will be achieved by delivering an optimized growth factor cascade to orchestrate chemotaxis, proliferation, and chondrogenic differentiation by endogenous MSC. We propose to test this hypothesis with the following specific aims: Aim 1: To induce chemotaxis by cells with chondrogenic potential, to expand their population, and to induce robust chondrogenesis in vitro. Aim 2: To design sequential, 3-stage growth factor delivery in vitro, Aim 3: To test our cartilage regeneration therapy in vivo in a rabbit mandibular condyle osteochondral defect, My TMJ cartilage regeneration approach is innovative because 1) engineered growth factor delivery will orchestrate chemotaxis, proliferation, and differentiation by endogenous sMSC and bMSC, 2) the therapy is based on rational design principles and developmental biology concepts, and 3) collagen network integration and maturation will be quantitatively characterized at the nano-scales. This therapy will be easily translated to the clinic to treat patients with TMJ cartilage injuries.